Small molecule inhibition of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens
The malaria parasite Plasmodium falciparum and related apicomplexan pathogens contain an essential plastid organelle, the apicoplast, which is a key anti-parasitic target. Derived from secondary endosymbiosis, the apicoplast depends on novel, but largely cryptic, mechanisms for protein/lipid import...
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| Format: | Article |
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eLife Sciences Publications, Ltd
2018
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| Online Access: | http://hdl.handle.net/1721.1/113561 https://orcid.org/0000-0003-0606-9896 https://orcid.org/0000-0002-1719-5399 |
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| author | Amberg-Johnson, Katherine Ganesan, Suresh M. Lorenzi, Hernan A. Niles, Jacquin C. Yeh, Ellen Hari, Sanjay B. Sauer, Robert T. |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Amberg-Johnson, Katherine Ganesan, Suresh M. Lorenzi, Hernan A. Niles, Jacquin C. Yeh, Ellen Hari, Sanjay B. Sauer, Robert T. |
| author_sort | Amberg-Johnson, Katherine |
| collection | MIT |
| description | The malaria parasite Plasmodium falciparum and related apicomplexan pathogens contain an essential plastid organelle, the apicoplast, which is a key anti-parasitic target. Derived from secondary endosymbiosis, the apicoplast depends on novel, but largely cryptic, mechanisms for protein/lipid import and organelle inheritance during parasite replication. These critical biogenesis pathways present untapped opportunities to discover new parasite-specific drug targets. We used an innovative screen to identify actinonin as having a novel mechanism-of-action inhibiting apicoplast biogenesis. Resistant mutation, chemical-genetic interaction, and biochemical inhibition demonstrate that the unexpected target of actinonin in P. falciparum and Toxoplasma gondii is FtsH1, a homolog of a bacterial membrane AAA+ metalloprotease. PfFtsH1 is the first novel factor required for apicoplast biogenesis identified in a phenotypic screen. Our findings demonstrate that FtsH1 is a novel and, importantly, druggable antimalarial target. Development of FtsH1 inhibitors will have significant advantages with improved drug kinetics and multistage efficacy against multiple human parasites. |
| first_indexed | 2024-09-23T15:42:10Z |
| format | Article |
| id | mit-1721.1/113561 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T15:42:10Z |
| publishDate | 2018 |
| publisher | eLife Sciences Publications, Ltd |
| record_format | dspace |
| spelling | mit-1721.1/1135612022-10-02T03:31:18Z Small molecule inhibition of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens Amberg-Johnson, Katherine Ganesan, Suresh M. Lorenzi, Hernan A. Niles, Jacquin C. Yeh, Ellen Hari, Sanjay B. Sauer, Robert T. Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Hari, Sanjay B. Sauer, Robert T. The malaria parasite Plasmodium falciparum and related apicomplexan pathogens contain an essential plastid organelle, the apicoplast, which is a key anti-parasitic target. Derived from secondary endosymbiosis, the apicoplast depends on novel, but largely cryptic, mechanisms for protein/lipid import and organelle inheritance during parasite replication. These critical biogenesis pathways present untapped opportunities to discover new parasite-specific drug targets. We used an innovative screen to identify actinonin as having a novel mechanism-of-action inhibiting apicoplast biogenesis. Resistant mutation, chemical-genetic interaction, and biochemical inhibition demonstrate that the unexpected target of actinonin in P. falciparum and Toxoplasma gondii is FtsH1, a homolog of a bacterial membrane AAA+ metalloprotease. PfFtsH1 is the first novel factor required for apicoplast biogenesis identified in a phenotypic screen. Our findings demonstrate that FtsH1 is a novel and, importantly, druggable antimalarial target. Development of FtsH1 inhibitors will have significant advantages with improved drug kinetics and multistage efficacy against multiple human parasites. National Institutes of Health (U.S.) (Award AI016892) National Institutes of Health (U.S.) (Award F32GM116241) 2018-02-09T17:16:50Z 2018-02-09T17:16:50Z 2017-08 2017-06 2018-02-02T19:08:02Z Article http://purl.org/eprint/type/JournalArticle 2050-084X http://hdl.handle.net/1721.1/113561 Amberg-Johnson,et al. “Small Molecule Inhibition of Apicomplexan FtsH1 Disrupts Plastid Biogenesis in Human Pathogens.” eLife 2017, 6 (August 2017): e29865 © Amberg-Johnson et al https://orcid.org/0000-0003-0606-9896 https://orcid.org/0000-0002-1719-5399 http://dx.doi.org/10.7554/ELIFE.29865 eLife Creative Commons Attribution 4.0 International License https://creativecommons.org/licenses/by/4.0/ application/pdf eLife Sciences Publications, Ltd eLife |
| spellingShingle | Amberg-Johnson, Katherine Ganesan, Suresh M. Lorenzi, Hernan A. Niles, Jacquin C. Yeh, Ellen Hari, Sanjay B. Sauer, Robert T. Small molecule inhibition of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens |
| title | Small molecule inhibition of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens |
| title_full | Small molecule inhibition of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens |
| title_fullStr | Small molecule inhibition of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens |
| title_full_unstemmed | Small molecule inhibition of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens |
| title_short | Small molecule inhibition of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens |
| title_sort | small molecule inhibition of apicomplexan ftsh1 disrupts plastid biogenesis in human pathogens |
| url | http://hdl.handle.net/1721.1/113561 https://orcid.org/0000-0003-0606-9896 https://orcid.org/0000-0002-1719-5399 |
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